The Phenotypic Spectrum of a Mutation Hotspot Responsible for the Short QT Syndrome

Hu, Dan; Li, Yang; Zhang, Jiancheng; Pfeiffer, Ryan; Gollob, Michael H.; Healey, Jeff S.; Harrell, Daniel Toshio; Makita, Naomasa; Abe, Haruhiko; Sun, Yaxun; Guo, Jihong; Zhang, Li; Yan, Gan‐Xin; Mah, Douglas Y.; Walsh, Edward P.; Leopold, Harris; Giustetto, Carla; Gaïta, Fiorenzo; Zienciuk-Krajka, Agnieszka; Mazzanti, Andrea; Priori, Silvia G.; Antzelevitch, Charles; Barajas-Martínez, Héctor

doi:10.1016/j.jacep.2016.11.013

Cited by 39 publications

(67 citation statements)

References 44 publications

(56 reference statements)

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“…The major clinical presentations are QT prolongation, supraventricular arrhythmia, ventricular arrhythmia, sinus node dysfunction, and conduction defect. Although we are more familiar with congenital SQTS, acquired forms of QT shorting have also been realized, such as digitalis toxicity, hyperkalemia, hypercalcemia, acidosis, or carnitine deficiency but drug‐induced SQTS was rarely reported. Our patient is the first acquired SQTS case induced by anticancer treatment to date.…”

Section: Discussionmentioning

confidence: 99%

“…Congenital short QT syndrome has been associated with mutations in potassium or calcium channels, which result in acceleration of the repolarization process and an abnormal abbreviation of the QT interval. 2 Acquired short QT syndrome is usually caused by acidosis, hypercalcemia, hyperkalemia, hypothermia, etc. Current evidence suggests the involvement of an increasing number of drugs in acquired forms of long QT and Brugada syndromes.…”

Section: Introductionmentioning

confidence: 99%

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Acquired short QT syndrome in a cancer patient treated with Toad

Huang

Xu²,

Barajas-Martínez

et al. 2019

Pacing Clinical Electrophis

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Although drug‐induced short QT syndrome (SQTS) has been recognized, we currently report the first acquired SQTS case induced by bufotalinin (toad, an antineoplastic drug), which is a traditional Chinese folk prescription. It has cross reaction with digoxin and affects the Na+‐K+‐ATPase, the SR Ca2+ release from ryanodine receptor‐2 (RyR2), the reactive oxygen species (ROS) production from the mitochondria. The case presented with bradycardia, extreme QT shortening, and sinoatrial block that were resolved after gastric lavage, rehydration, electrolyte (hyperkalemia, hyponatremia, hypocalcemia) correction, and atropine injection. Clinicians should recognize a potential association between toad poisoning and SQTS from this case.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Acquired short QT syndrome in a cancer patient treated with Toad

Huang

Xu²,

Barajas-Martínez

et al. 2019

Pacing Clinical Electrophis

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“…Around 200 cases of SQTS have been reported in the literature [21]. One recent analysis listed 27 probands with genetic mutation [22], whilst another considered a total of 132 reported cases [15]. In the nearly two decades since the identification of congenital SQTS there has not been an accumulation of cases to mirror that of the long QT syndrome.…”

Section: Complexities In the Diagnosis Of The Sqtsmentioning

confidence: 99%

Learning from studying very rare cardiac conditions: the example of short QT syndrome

Hancox

Whittaker

Zhang

et al. 2019

J Congenit Heart Dis

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Background: Some congenital heart conditions are very rare. In a climate of limited resources, a viewpoint could be advanced that identifying diagnostic criteria for such conditions and, through empiricism, effective treatments should suffice and that extensive mechanistic research is unnecessary. Taking the rare but dangerous short QT syndrome (SQTS) as an example, this article makes the case for the imperative to study such rare conditions, highlighting that this yields substantial and sometimes unanticipated benefits. Genetic forms of SQTS are rare, but the condition may be under-diagnosed and carries a risk of sudden death. Genotyping of SQTS patients has led to identification of clear ion channel/transporter culprits in < 30% of cases, highlighting a role for as yet unidentified modulators of repolarization. For example, recent exome sequencing in SQTS has identified SLC4A3 as a novel modifier of ventricular repolarization. The need to distinguish "healthy" from "unhealthy" short QT intervals has led to a search for additional markers of arrhythmia risk. Some overlap may exist between SQTS, Brugada Syndrome, early repolarization and sinus bradycardia. Genotype-phenotype studies have led to identification of arrhythmia substrates and both realistic and theoretical pharmacological approaches for particular forms of SQTS. In turn this has increased understanding of underlying cardiac ion channels. In silico and pharmacological data have highlighted risks with abbreviation of refractoriness accompanied by local dispersion of repolarization, and this urges caution with the deployment of K + channel activation as a novel antiarrhythmic approach. The association between abbreviated QT c intervals and primary carnitine deficiency, particularly in patients with concomitant cardiomyopathy illustrates a link between metabolism and electrogenesis, in which the correct identification of causation could, in some cases, lead to dietary intervention that may obviate the need for antiarrhythmic or heart failure drugs. Conclusions: As illustrated here for the SQTS, the detailed study of rare disorders is both directly beneficial for the treatment/management of affected patients and for increasing the understanding of associated underlying cardiac physiology and pharmacology. The pursuit of underlying gene mutations can lead to unanticipated new links between particular genes and cardiac electrophysiology, opening new avenues for research and potential therapeutic intervention.

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“…Other antiarrhythmics such as carvediol, metoprolol, and sotalol do not have the same effect as hydroquinidine (El-Battrawy et al, 2018a). However, hydroquinidine might not be effective in all SQTS types and its effect might be genotype dependent (McPate et al, 2005;McPate et al, 2008;Hu et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…However, the most frequent described type is SQTS 1. In some cases, overlap syndromes, like SQTS accompanied with Brugada syndrome (BrS), have been reported (McPate et al, 2005;Hu et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Differences in Short QT Syndrome Subtypes: A Systematic Literature Review and Pooled Analysis

El‐Battrawy

Schlentrich

et al. 2020

Front. Genet.

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Background: Short QT syndrome (SQTS) is a rare syndrome and affects different types of genes. However, data on differences of clinical profile and outcome of different SQTS types are sparse. Methods: We conducted a pooled analysis of 110 SQTS patients. Patients have been diagnosed between 2000 and 2017 at our institution (n = 12) and revealed using a literature review (n = 98). 29 studies were identified by analysing systematic data bases (PubMed, Web of Science, Cochrane Libary, Cinahl). Results: 67 patients with genotype positive SQTS origin and 43 patients with genotype negative origin were found. A significant difference is documented between the sex with a higher predominance of male in genotype negative SQTS patients and predominance of females in genotype positive SQTS patients (male 52% versus 84%, female 45% versus 14%; p = 0.0016). No relevant difference of their median age (genotype positive 27 ± 19 versus genotype negative 29 ± 15; p = 0.48) was found. Asymptomatic patients and patients reporting symptoms such as syncope, sudden cardiac death, atrial flutter and ventricular fibrillation documented in both groups were similar except atrial fibrillation (genotype positive 19% versus genotype negative 0%; p = 0.0055). The QTc interval was not significantly different in both groups (genotype positive 315 ± 32 versus genotype negative 320 ± 19; p = 0.30). The treatments (medical treatment and ICD implantation) in both groups were comparable. Electrophysiology studies were not significantly higher documented in patients with genotype positive and negative origin (24% versus 9%; p = 0.075). Events at follow up such as VT, VF, and SCD were not higher presented in patients with genotype positive (13% versus 9%) (p = 0.25). 54% of genotype positive SQTS patients showed SQTS 1 followed by STQS 2 (21%) and SQTS 3 (10%). Conclusions: The long-term risk of a malignant arrhythmic event is not higher in patients with genotype positive. However, patients with genotype positive present themselves more often with AF with a female predominance. Also, other events at follow up such as syncope, atrial flutter and palpitation were not significantly higher (9% versus 0%; p = 0.079).

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The Phenotypic Spectrum of a Mutation Hotspot Responsible for the Short QT Syndrome

Abstract: We reported the clinical characteristics and biophysical properties of the highly frequent mutation that contributes to genetically identified SQTS probands. These findings extend our understanding of the spectrum of KCNH2 channel defects in SQTS.

Cited by 39 publications

References 44 publications

Acquired short QT syndrome in a cancer patient treated with Toad

Acquired short QT syndrome in a cancer patient treated with Toad

Learning from studying very rare cardiac conditions: the example of short QT syndrome

Differences in Short QT Syndrome Subtypes: A Systematic Literature Review and Pooled Analysis

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